Sulfonamide derivatives

ABSTRACT

The present invention is directed to a new class of 6-sulfonamide quinoline and chromene derivative and to their use as androgen antagonists.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/456,316 filed Mar. 20, 2003.

FIELD OF THE INVENTION

The present invention is directed to a new class of quinolin-2-ones andchromen-2-ones (hereinafter “quinolines and chromenes”), to their use asandrogen receptor antagonists, to medicinals containing these compoundsand to their use to alleviate conditions associated with inappropriateactivation of the androgen receptor.

BACKGROUND OF THE INVENTION

The androgen receptor (AR) is a member of the steroid receptor (SR)family of transcriptional regulatory proteins that transduces thesignaling information conveyed by androgens. Upon androgen binding, theandrogen receptor is released from the repressive effects of an Hsp90-based regulatory complex, allowing the receptor to either activate orinhibit transcription of target genes in a hormone-dependent manner. Inaddition to the role the androgen receptor plays in male sexdetermination, its activation plays a critical role in the developmentand progression of benign prostate hyperplasia, prostate cancer,seborrhea, acne, premenstrual syndrome, lung cancer, ovarian polycyclicsyndrome, hirsutism, and hair loss. Thus, the androgen receptor is animportant target in multiple areas of drug discovery.

U.S. Pat. No. 6,017,924 discloses a class of non-steroidal compounds,pyridinoquinolines that have affinity for the androgen receptor. The'924 patent describes these compounds as being agonists, partialagonists, antagonists, and partial antagonists, etc. The '924 patentprovides no guidance on how to achieve a specific biological effect(i.e. agonist versus antagonist). Agonists have the ability tomasculinize females, whereas antagonists feminize males. Such sideeffects limit the potential applicability of androgen therapy.

PCT applications WO 01/16133 and WO 01/16139 also disclose non-steroidalcompounds that have affinity for the androgen receptor. Examples of suchstructures include pyrazinoquinolines, oxazinoquinolines, andpyridinoquinolines. The PCT application does not disclose any6-sulfonamido-quinolin-2-ones or 6-sulfonamido-chromen-2-ones.

PCT application WO 01/16108 discloses non-steroidal compounds havingaffinity for the androgen receptor. Like the '924 patent describedabove, the compounds are described as having both agonist and antagonisteffects. Some of the compounds of the PCT application are quinolin-2-onederivatives. The PCT application does not disclose any6-sulfonamido-quinolin-2-ones or 6-sulfonamido-chromen-2-ones.

While the prior art describes compounds having affinity for the androgenreceptor, it does not describe how to achieve selectivity with respectto this affinity (i.e. agonist or antagonist). The physiological impactof this affinity is often an undesirable side effect, depending upon thegender of the patient. Thus a need exists in the art for androgenreceptor antagonists.

SUMMARY OF THE INVENTION

In accordance with the present invention a new class of androgenantagonists have been discovered. These compounds may be represented bythe following formula:

in which:

-   -   a. M is NZ or O;    -   b. Z is represented by H or C₁-C₄ alkyl;    -   c. R¹ is represented by hydrogen, (C₁-C₂)alkyl, optionally        substituted with one or more halogens, or (C₁-C₂)alkoxy,        optionally substituted with 1 or more halogens;    -   d. R² is absent, or may represent up to 2 substituents selected        from the group consisting of halogen, nitrile, hydroxy,        (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,        (C₁-C₂)alkyl substituted with 1 or more halogens, (C₁-C₂)alkoxy        substituted with one or more halogens, SR⁴, and NR⁴R⁵;    -   e. R⁴ is represented by hydrogen, optionally substituted phenyl,        (C₁-C₄)alkyl, or optionally substituted benzyl;    -   f. R⁵ is represented by optionally substituted phenyl,        optionally substituted heteroaryl, or optionally substituted        heterocyclic;    -   g. A and B are each independently represented by a substituent        selected from the group consisting of hydrogen, (C₁-C₆)alkyl        optionally substituted with one or more halogens,        (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, optionally substituted (C₃-C8)        cycloalkyl, optionally substituted (C₅-C₈) cycloalkenyl,        optionally substituted phenyl, optionally substituted        cycloalkylphenyl, optionally substituted heterocyclic,        optionally substituted heteroaryl, (C₁-C₆)alkylR⁶,        —(CH₂)_(m)—R⁷—Y[—CH₂]_(n)—X—R⁸, —(CH₂)_(q)CHX¹X²;    -   h. R⁶ is represented by a substituent selected from the group        consisting of nitrile, OH, optionally substituted phenyl,        optionally substituted cyloalkylphenyl, optionally substituted        heterocyclic, optionally substituted heteroaryl, optionally        substituted (C₃-C₈) cycloalkyl, optionally substituted (C₅-C₈)        cycloalkenyl, SR⁴, NR⁴R⁵    -   i. R⁷ is absent, or is represented by a substituent selected        from the group consisting of optionally substituted (C₃-C₈)        cycloalkyl, optionally substituted (C₅-C₈) cycloalkenyl,        optionally substituted heteroaryl, optionally substituted        heterocyclic, and optionally substituted phenyl,    -   j. R⁸ is absent, or is represented by a substituent selected        from the group consisting of (C₁-C₆)alkyl optionally substituted        with one or more halogens, optionally substituted (C₃-C8)        cycloalkyl, optionally substituted (C₅-C₈) cycloalkenyl,        optionally substituted heteroaryl, optionally substituted        heterocyclic, optionally substituted phenyl, and optionally        substituted cycloalkylphenyl;    -   k. m is an integer selected from 0, 1, 2, 3, or 4;    -   Y is absent, or is represented by O, C(O), C(O)O, CH₂C(O)O, OH,        SH, or S;    -   m. n is represented by an integer selected from 0, 1, 2, 3, or        4;    -   n. X is absent, or is represented by O, C(O), C(O)O, —CH₂C(O)O,        OH, SH or S    -   o. q is represented by an integer selected from 0, 1, 2, 3, or        4;    -   p. X¹ is represented by a substituent selected from the group        consisting of optionally substituted (C₃-C₈) cycloalkyl,        optionally substituted (C₅-C₈) cycloalkenyl, optionally        substituted heteroaryl, optionally substituted heterocyclic,        optionally substituted phenyl, and optionally substituted        cycloalkylphenyl;    -   q. X² is represented by a substituent selected from the group        consisting of optionally substituted (C₃-C₈) cycloalkyl,        optionally substituted (C₅-C₈) cycloalkenyl, optionally        substituted heteroaryl, optionally substituted heterocyclic,        optionally substituted phenyl, and optionally substituted        cycloalkylphenyl and;    -   r. the pharmaceutically acceptable salts, solvates, and prodrugs        thereof.

The compounds of Formula I are androgen receptor antagonists. Thecompounds will inhibit, or decrease, activation of the androgen receptorby androgens. The compounds can be used to treat, or alleviate,conditions associated with inappropriate activation of the androgenreceptor. Examples of such conditions include, but are not limited to,acne, excess seborrhea secretion, alopecia, prostrate cancer, hirsutism,etc.

The invention is also directed to pharmaceutical compositions containingat least one of the compounds of Formula I, in an amount effective todecrease activation of the androgen receptor. In a further embodiment,the invention is directed to an article of manufacture containing acompound of Formula I, packaged for retail distribution, in associationwith instructions advising the consumer on how to use the compound toalleviate a condition associated with inappropriate activation of theandrogen receptor. An additional embodiment is directed to the use of acompound of Formula I as a diagnostic agent to detect inappropriateactivation of the androgen receptor.

In a further embodiment, the compounds of Formula I are used topicallyto induce and/or stimulate hair growth and/or to slow down hair loss.The compounds may also be used topically in the treatment ofhyperseborrhoea and/or of acne.

DETAILED DESCRIPTION OF THE INVENTION

The headings within this document are only being utilized to expediteits review by the reader. They should not be construed as limiting theinvention or claims in any manner.

Definitions and Exemplification

As used throughout this application, including the claims, the followingterms have the meanings defined below, unless specifically indicatedotherwise. The plural and singular should be treated as interchangeable,other than the indication of number:

-   -   a. “C₁-C₄ alkyl” and “lower alkyl” refers to a branched or        straight chained alkyl group containing from 1 to 4 carbon        atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,        isobutyl, etc.    -   b. “C₁-C₆ alkyl” refers to a branched or straight chained alkyl        group containing from 1 to 6 carbon atoms, such as methyl,        ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl,        isopentyl, n-hexyl, etc.    -   c. “halogen” refers to a chlorine, fluorine or bromine atom.    -   d. “C₁-C₂ alkyl substituted with one or more halogen atoms”        refers to a straight chained alkyl group containing 1 or 2        carbon atoms, i.e. methyl or ethyl, in which at least one        hydrogen atom is replaced with a halogen. Examples include        chloromethyl, difluoromethyl, trifluoromethyl, etc.    -   e. “lower alkoxy group” and “C₁-C₄ alkoxy” refers to a straight        or branched chain alkoxy group containing from 1 to 4 carbon        atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,        isobutoxy, etc.    -   f. “C₂-C₄ alkenyl” refers to a straight-chain or branched-chain        hydrocarbon radical containing from 2 to 4 carbon atoms and 1,        or more, carbon-carbon double bonds. Examples of alkenyl        radicals include ethenyl, propenyl, 1,4-butadienyl and the like.    -   g. “C₂-C₆ alkenyl” refers to a straight-chain or branched-chain        hydrocarbon radical containing from 2 to 6 carbon atoms and 1,        or more, carbon-carbon double bonds. Examples of alkenyl        radicals include ethenyl, propenyl, 1,4-butadienyl, pentenyl,        hexenyl and the like.    -   h. “C₂-C₄ alkynyl” refers to a straight-chain or branched-chain        hydrocarbon radical containing from 2 to 4 carbon atoms and        having 1, or more, carbon-carbon triple bonds. Examples of        alkynyl radicals include ethynyl, propynyl, butynyl and the        like.    -   i. “C₂-C₆ alkynyl” refers to a straight-chain or branched-chain        hydrocarbon radical containing from 2 to 6 carbon atoms and        having 1, or more, carbon-carbon triple bonds. Examples of        alkynyl radicals include ethynyl, propynyl, butynyl, pentynyl,        hexynyl and the like.    -   j. “(C₁-C₄)alkylnitrile” refers to a straight-chain or branched        chain alkyl group containing from 1 to 4 carbon atoms in which        at least one hydrogen atom is replaced with a C≡N moiety.    -   k. “(C₁-C₄)alkanol” refers to a straight-chain or branched        chained alkyl group containing from 1 to four carbon atoms group        in which at least one hydrogen atom is replaced with a hydroxy        function.    -   l. “optionally substituted phenyl” refers to a phenyl (C₆H₅)        which is substituted with up to 3 substituents, each substituent        is independently selected from the group consisting of halogen,        nitrile, hydroxy, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,        (C₁-C₄)alkoxy, (C₁-C₂)alkyl substituted with one or more        halogens, (C₁-C₂)alkoxy substituted with one or more halogens,        (C₁-C₄)alkylnitrile, (C₁-C₄)alkanol, SR⁴, and NR⁴R⁵. These        substituents may be the same or different and may be located at        any of the ortho, meta, or para positions.    -   m. “optionally substituted benzyl” refers to a benzyl        —CH₂—(C₆H₅) which is substituted with up to 3 substituents, each        substituent is independently selected from the group consisting        of halogen, nitrile, hydroxy, (C₁-C₄)alkyl, (C₂-C₄) alkenyl,        (C₂-C₄) alkynyl (C₁-C₄)alkoxy, (C₁-C₂)alkyl substituted with one        or more halogens, (C₁-C₂)alkoxy substituted with one or more        halogens, (C₁-C₄)alkylnitrile, (C₁-C₄)alkanol, SR⁴, and NR⁴R⁵.        These substituents may be the same or different and may be        located at any of the ortho, meta, or para positions.    -   n. (C₁-C₂)alkoxy substituted with one or more halogen atoms        refers to a straight chained alkoxy group containing 1 or 2        carbon atoms, ie, methoxy or ethoxy in which at least one        hydrogen atom is replaced with a halogen.    -   o. “heteroaryl” refers to aromatic ring having one, or more,        heteroatoms selected from oxygen, nitrogen and sulfur. More        specifically, it refers to a 5- or 6-, membered ring containing        1, 2, or 3 nitrogen atoms; 1 oxygen atom; 1 sulfur atom; 1        nitrogen and 1 sulfur atom; 1 nitrogen and 1 oxygen atom; 2        nitrogen atoms and 1 oxygen atom; or 2 nitrogen atoms and 1        sulfur atom. The 5-membered ring has 2 double bonds and the        6-membered ring has 3 double bonds. The term heteroaryl also        includes bicyclic groups in which the heteroaryl ring is fused        to a benzene ring, heterocyclic ring, a cycloalkyl ring, or        another heteroaryl ring. Examples of such heteroaryl ring        systems include, but are not limited to pyrrolyl, benzothienyl,        benzofuryl, quinolyl, isoquinolyl, furanyl, thienyl, imidazolyl,        oxazolyl, indolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl,        purinyl, quinolinyl, and isoquinolinyl.    -   p. “optionally substituted heteroaryl” refers to a heteroaryl        moiety as defined immediately above, in which up to 2 carbon        atoms of the heteroaryl moiety may be substituted with a        substituent, each substituent is independently selected from the        group consisting of halogen, nitrile, hydroxy, (C₁-C₄)alkyl,        (C₂-C₄)alkenyl, (C₂-C₄)alkynyl , (C₁-C₄)alkoxy, (C₁-C₂)alkyl        substituted with one or more halogens, (C₁-C₂)alkoxy substituted        with one or more halogens, (C₁-C₄)alkylnitrile , (C₁-C₄)alkanol,        SR⁴, and NR⁴R⁵. Further, any nitrogen atom of the heterocyclic        ring may be substituted with a (C₁-C₄)alkyl.    -   q. “heterocycle” or “heterocyclic ring” refers to any 3- or        4-membered ring containing a heteroatom selected from oxygen,        nitrogen and sulfur; or a 5-, 6-, 7-, 8-, 9-, or 10-membered        ring containing 1, 2, or 3 nitrogen atoms; 1 oxygen atom; 1        sulfur atom; 1 nitrogen and 1 sulfur atom; 1 nitrogen and 1        oxygen atom; 2 oxygen atoms in non-adjacent positions; 1 oxygen        and 1 sulfur atom in non-adjacent positions; or 2 sulfur atoms        in non-adjacent positions. The 5-membered ring has 0 to 1 double        bonds, the 6- and 7-membered rings have 0 to 2 double bonds, and        the 8, 9, or 10 membered rings may have 0, 1, 2, or 3 double        bonds. The term “heterocyclic” also includes bicyclic groups in        which any of the above heterocyclic rings is fused to a benzene        ring, a cyclohexane or cyclopentane ring or another heterocyclic        ring (for example tetrahydroquinolyl, dihydrobenzofuryl and the        like). Heterocyclics include: pyrrolidinyl, tetrahydrofuranyl,        tetrahydrothiophenyl, piperidinyl, piperazinyl, azepane,        azocane, morpholinyl, and quinolinyl.    -   r. “optionally substituted heterocyclic” refers to a        heterocyclic moiety as defined immediately above, in which up to        2 carbon atoms of the heterocycle moiety may be substituted with        a substituent, each substituent is independently selected from        the group consisting of halogen, nitrile, hydroxy, (C₁-C₄)alkyl,        (C₂-C₄) alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy, (C₁-C₂)alkyl        substituted with one or more halogens, (C₁-C₂)alkoxy substituted        with 1 or more halogens, (C₁-C₄)alkylnitrile, (C₁-C₄)alkanol,        (═O), SR⁴, and NR⁴R⁵. Further, any nitrogen atom of the        heterocyclic ring may be substituted with a (CI-C₄)alkyl.    -   s. “C₃-C₈ cycloalkyl” refers to a saturated or partially        saturated monocyclic, bicyclic or tricyclic alkyl radical        wherein each cyclic moiety has about 3 to about 8 carbon atoms.        Examples of cyclcoalkyl radicals include cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like.    -   t. “optionally substituted “C₃-C₈ cycloalkyl” refers to a        cycloalkyl moiety as defined immediately above in which up to 3        hydrogen atoms of the cycloalkyl moiety may be replaced with a        substituent, each substituent is independently selected from the        group consisting of halogen, nitrile, hydroxy, (C₁-C₄)alkyl,        (C₂-C₄)alkenyl, (C₂-C₄)alkynyl , (C₁-C₄)alkoxy, (C₁-C₂)alkyl        substituted with one or more halogens, (C₁-C₂)alkoxy substituted        with one or more halogens, (C₁-C₄)alkylnitrile, (C₁-C₄)alkanol,        SR⁴, and NR⁴R⁵.    -   u. “C₅-C₈ cycloalkenyl” refers to a partially saturated        monocyclic, bicyclic or tricyclic alkyl radical containing 1, or        more, carbon-carbon double bonds, wherein each cyclic moiety has        about 5 to about 8 carbon atoms. Examples of cyclcoalkenyl        radicals include cyclopentenyl, cyclohexenyl, and the like    -   v. “optionally substituted “C₅-C₈ cycloalkenyl” refers to a        cycloalkenyl moiety as defined immediately above, in which up to        3 hydrogen atoms of the cycloalkenyl moiety may be replaced with        a substituent, each substituent is independently selected from        the group consisting of halogen, nitrile, hydroxy, (C₁-C₄)alkyl,        (C₂-C₄)alkenyl, (C₂-C₄)alkynyl , (C₁-C₄)alkoxy, (C₁-C₂)alkyl        substituted with one or more halogens, (C₁-C₂)alkoxy substituted        with one or more halogens, (C₁-C₄)alkylnitrile, (C₁-C₄)alkanol,        SR⁴, and NR⁴R⁵.    -   w. “cycloalkylphenyl” refers to a phenyl ring in which two        carbon atoms of the phenyl ring complete a cyclobutyl,        cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl ring.        Examples of such cycloalkylphenyl moieties include: indanyl,        tetrahydronapthyl, and the like.    -   x. “optionally substituted cycloalkylphenyl” refers to a        cycloalkylphenyl moiety as described above, in which up to 3        hydrogen atoms of the cycloalkylphenyl moiety may be replaced by        a substituent, each substituent is independently selected from        the group consisting of halogen, nitrile, hydroxy, (C₁-C₄)alkyl,        C₂-C₄ alkenyl, C₂-C₄ alkynyl, (C₁-C₄)alkoxy, (C₁-C₂)alkyl        substituted with one or more halogens, (C₁-C₂)alkoxy substituted        with one or more halogens, (C₁-C₄)alkylnitrile, (C₁-C₄)alkanol,        SR⁴, and NR⁴R⁵.    -   y. “androgen” refers to testosterone and its precursors and        metabolites, and 5-alpha reduced androgens, including but not        limited to dihydrotestosterone. Androgen refers to androgens        from the testis, adrenal gland, and ovaries, as well as all        forms of natural, synthetic and substituted or modified        androgens.    -   z. “pharmaceutically acceptable salts” is intended to refer to        either pharmaceutically acceptable acid addition salts” or        “pharmaceutically acceptable basic addition salts” depending        upon actual structure of the compound.    -   aa. “pharmaceutically acceptable acid addition salts” is        intended to apply to any non-toxic organic or inorganic acid        addition salt of the base compounds represented by Formula I or        any of its intermediates. Illustrative inorganic acids which        form suitable salts include hydrochloric, hydrobromic,        sulphuric, and phosphoric acid and acid metal salts such as        sodium monohydrogen orthophosphate, and potassium hydrogen        sulfate. Illustrative organic acids, which form suitable salts        include the mono-, di-, and tricarboxylic acids. Illustrative of        such acids are for example, acetic, glycolic, lactic, pyruvic,        malonic, succinic, glutaric, fumaric, malic, tartaric, citric,        ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic,        phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic,        p-toluenesulfonic acid, and sulfonic acids such as methane        sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can        exist in either a hydrated or substantially anhydrous form. In        general, the acid addition salts of these compounds are soluble        in water and various hydrophilic organic solvents, and which in        comparison to their free base forms, generally demonstrate        higher melting points.    -   bb. “pharmaceutically acceptable basic addition salts” is        intended to apply to any non-toxic organic or inorganic basic        addition salts of the compounds represented by Formula I, or any        of its intermediates. Illustrative bases which form suitable        salts include alkali metal or alkaline-earth metal hydroxides        such as sodium, potassium, calcium, magnesium, or barium        hydroxides; ammonia, and aliphatic, alicyclic, or aromatic        organic amines such as methylamine, dimethylamine,        trimethylamine, and picoline.    -   cc. “prodrug” refers to compounds that are rapidly transformed        in vivo to yield the parent compound of the above formulas, for        example, by hydrolysis in blood. A thorough discussion is        provided in T. Higuchi and V. Stella, “Pro-drugs as Novel        Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and        in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,        American Pharmaceutical Association and Pergamon Press, 1987,        both of which are incorporated herein by reference.    -   dd. “compound of Formula I” “compounds of the invention” and        “compounds” are used interchangeably throughout the application        and should be treated as synonoms.    -   ee. “patient” refers to warm blooded animals such as, for        example, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs,        monkeys, chimpanzees, and humans.    -   ff. “treat” refers to the ability of the compounds to either        relieve, alleviate, or slow the progression of the patient's        disease (or condition) or any tissue damage associated with the        disease.

Some of the compounds of Formula I will exist as optical isomers. Anyreference in this application to one of the compounds represented byFormula I is meant to encompass either a specific optical isomer or amixture of optical isomers (unless it is expressly excluded). Thespecific optical isomers can be separated and recovered by techniquesknown in the art such as chromatography on chiral stationary phases orresolution via chiral salt formation and subsequent separation byselective crystallization. Alternatively utilization of a specificoptical isomer as the starting material will produce the correspondingisomer as the final product.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

Some of the compounds of Formula I are based upon a6-sulfonamido-quinolin-2-one nucleus. To further exemplify the inventionthis ring is depicted below along with its numbering system:

Position 1 of the quinoline nucleus contains a nitrogen atom. Thisnitrogen atom may be substituted with a lower alkyl group as describedabove. Position 6 of the quinoline ring will always be substituted witha SO₂ moiety as depicted in FIG. 1. Any of positions 3, 5, 7, or 8 ofthe quinoline nucleus may optionally be substituted with a substituentfrom the list described for R². Up to two of these positions may besubstituted. Position 4 of the quinoline nucleus may optionally besubstituted with 1 of the halogenated lower alkyl or alkoxy moietiesdescribed for R¹ above. Typically, Position 4 will be substituted with atrifluoromethyl function.

The remaining compounds of Formula I are based upon a6-sulfonamido-2-oxo-chromene nucleus. To further exemplify theinvention, this ring is depicted below along with its numbering system:

Position 1 of the chromene nucleus contains an oxygen atom. Position 6of the chromene ring will always be substituted with a SO₂ moiety asdepicted in FIG. 1. Any of Positions 3, 5, 7, or 8 of the chromenenucleus may optionally be substituted with a substituent from the listdescribed for R₂. Up to two of these positions may be substituted.Position 4 of the chromene nucleus may optionally be substituted withone of the halogenated lower alkyl or alkoxy moieties described for R¹above. Typically, Position 4 will be substituted with a trifluoromethylfunction.

More specific embodiments of the invention are directed to compounds ofFormula I in which:

-   -   a. M is NZ, in which Z is H; R¹ is trifluoromethyl, R² is        absent, B is hydrogen, and A is represented by phenyl, which may        be optionally substituted.    -   b. M is NZ, in which Z is H, R¹ is trifluoromethyl, R² is        absent, B is hydrogen, or C₁-C₆ alkyl and A is C₁-C₆ alkyl, more        typically C₁-C₃ alkyl.    -   c. M is NZ, in which Z is H, R¹ is trifluoromethyl, R² is        absent, B is hydrogen, A is C₁-C₆ alkyl R⁶, and more        specifically a C₁-C₃ alkylphenyl ring.    -   d. M is NZ, in which Z is H, R¹ is trifluoromethyl, R² is        absent, B is hydrogen, A is C₁-C₆ alkylR⁶, and R⁶ is phenyl,        which has been substituted with trifluoromethyl, or C₁-C₄alkyl,        more specifically ethyl.    -   e. M is NZ in which Z is H, R¹ is trifluoromethy, R² is absent,        B is hydrogen, A is C₁-C₆ alkylR⁶, and R⁶ is cycloalkenyl,        typically cyclohexenyl.    -   f. M is NZ in which Z is H, R¹ is trifluoromethyl, R² is absent,        B is hydrogen, A is C₁-C₆ alkylR⁶, and R⁶ is cycloalkylphenyl.    -   g. M is NZ in which Z is H, R¹ is trifluoromethyl, R² is absent,        B is hydrogen, A is C₁-C₆ alkylR⁶, and R⁶ is heterocyclic.    -   h. M is NZ in which Z is H, R¹ is trifluoromethyl, R² is absent,        B is hydrogen, A is C₁-C₆ alkylR⁶, and R⁶ is heteroaryl.        Synthesis

The compounds of formula can be prepared using methods analogous tothose known in the art for the preparation of sulfonamides. The reader'sattention is directed to J. March, Advanced Organic Chemistry, 3^(rd)edition, page 445, John Wiley & Sons (1985) for a more detaileddiscussion of such synthesis. Scheme I below provides a generaloverview:

As depicted above, one of the starting materials is an appropriatelysubstituted quinolin-2-one or 2-oxo-chromene (i.e. R¹, R², and M are asin desired compound) that has been functionalized at the 6-position witha sulfonyl chloride moiety (Formula II). These compounds may be producedby introducing the sulfonyl chloride moiety into the 6-postion of thequinolin-2-ones and 2-oxo-chromenes by chlorosulfonation withchlorosulfonic acid at about 140° C. These reactions are described inmore detail in the working examples. The reader's attention is alsodirected to Furniss et al, Vogel's Textbook of Practical OrganicChemistry, 5^(th) Edition, pages 877-879, where such reactions aredescribed in detail.

The other starting material is an appropriately substituted amine asdescribed by Formula III (i.e. A and B are as in final compound). Theseamines can typically be purchased from Aldrich, which has an officelocated in St. Louis, Mo. USA. Further information may be obtained fromAldrich at, www.sigmaaldrich.com

The sulfonamides derivatives of Formula I are prepared by reacting thesulfonyl chloride derivative of Formula II with the appropriate amine asdescribed by Formula III in the presence of a non-nucleophilic base,such as pyridine or diisopropylethylamine, at about room temperature inan aprotic solvent, such as, N,N′-dimethylformamide. The reaction isallowed to proceed to completion, which is typically accomplished infrom 2 to 24 hours. If desired, the compounds can be isolated andpurified using techniques known in the art such as extraction and flashchromatography. These reactions are described in detail in the workingexamples.

Medical and Cosmetic Uses

The compounds of Formula I are androgen receptor antagonists. They canbe used to alleviate any condition associated with inappropriateactivation of the androgen receptor. Examples of such conditions includeprostate carcinomas, benign hyperplasia of the prostate, acne,hirsutism, seborrhoea, alopecia, premenstrual syndrome, lung cancer, andprecocious puberty.

In order to exhibit the therapeutic properties described above, thecompounds need to be administered in a quantity sufficient to inhibitactivation of the androgen receptor. This antagonistic amount can varydepending upon the particular disease/condition being treated, theseverity of the patient's disease/condition, the patient, the particularcompound being administered, the route of administration, and thepresence of other underlying disease states within the patient, etc.When administered systemically, the compounds typically exhibit theireffect at a dosage range of from about 0.1 mg/kg/day to about 100mg/kg/day for any of the diseases or conditions listed above. Repetitivedaily administration may be desirable and will vary according to theconditions outlined above.

The compounds of the present invention may be administered by a varietyof routes. They are effective if administered orally. The compounds mayalso be administered parenterally (i.e. subcutaneously, intravenously,intramuscularly, intraperitoneally, or intrathecally), rectally, ortopically.

In a typical embodiment, the compounds are administered topically.Topical administration is especially appropriate for hirsutism,alopecia, acne and hyperseborhhea. The dose will vary, but as a generalguideline, the compound will be present in a dermatologically acceptablecarrier in an amount of from 0.1 to 10 w/w % and the dermatologicalpreparation will be applied to the affected area from 1 to 4 timesdaily. “Dermatologically acceptable” refers to a carrier which may beapplied to the skin or hair, and which will allow the drug to diffuse tothe site of action. More specifically, it refers to the site whereinhibition of activation of an androgen receptor is desired. In afurther embodiment, the compounds are used topically to relievealopecia, especially androgenic alopecia. Androgens have a profoundeffect on both hair growth and hair loss. In most body sites, such asthe beard and pubic skin, androgens stimulate hair growth by prolongingthe growth phase of the hair cycle (anagen) and increasing folliclesize. Hair growth on the scalp does not require androgens but,paradoxically, androgens are necessary for balding on the scalp ingenetically predisposed individuals (androgenic alopecia) where there isa progressive decline in the duration of anagen and in hair folliclesize. Men castrated before puberty fail to grow beards and do not gobald. If subsequently treated with testosterone about one third of malecastrates will show balding. Androgeneic alopecia is also common inwomen where it usually present as a diffuse hair loss rather thanshowing the patterning seen in men.

As used in this application “alopecia” refers to partial or completehair loss on the scalp. The compounds will typically be used toalleviate androgenic alopecia. This condition afflicts both men andwomen. In males, the hair loss begins in the lateral frontal areas orover the vertex. For females, it is typically associated with thinningof the hair in the frontal and parietal regions. Complete hair loss infemales is rare.

While the compounds will most typically be used to alleviate androgenicalopecia, the invention is not limited to this specific condition. Thecompounds may be used to alleviate any type of alopecia. Examples ofnon-androgenic alopecia include alopecia areata, alopecia due toradiotherapy or chemotherapy, scarring alopecia, stress relatedalopecia, etc.

Thus, the compounds can be applied topically to the scalp and hair toprevent, or alleviate balding. Further, the compound can be appliedtopically in order to induce or promote the growth of hair on the scalp.

In a further embodiment of the invention, a compound of Formula I isapplied topically in order to prevent the growth of hair in areas wheresuch hair growth is not desired. One such use will be to alleviatehirsutism. Hirsutism is excessive hair growth in areas that typically donot have hair (i.e. a female face). Such inappropriate hair growthoccurs most commonly in women and is frequently seen at menopause. Thetopical administration of the compounds will alleviate this conditionleading to a reduction, or elimination of this inappropriate, orundesired, hair growth.

The compounds may also be used topically to decrease seborrheaproduction and more specifically to alleviate hyperseborrhoea (oilyskin). Likewise the compounds can be used topically alleviate acne.

Formulations

If desired, the compounds can be administered directly without anycarrier. However, to ease administration, they will typically beformulated into pharmaceutical carriers. Likewise, they will mosttypically be formulated into dermatological, or cosmetic carriers. Inthis application the terms “dermatological carrier” and “cosmetic”carrier are being used interchangeably. They refer to formulationsdesigned for administration directly to the skin or hair.

Pharmaceutical and cosmetic compositions can be manufactured utilizingtechniques known in the art. Typically an antagonistic amount of thecompound will be admixed with a pharmaceutically/cosmetically acceptablecarrier.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, lozenges, melts,powders, suspensions, or emulsions. Solid unit dosage forms can becapsules of the ordinary gelatin type containing, for example,surfactants, lubricants and inert fillers such as lactose, sucrose, andcornstarch or they can be sustained release preparations.

In another embodiment, the compounds of Formula I can be tableted withconventional tablet bases such as lactose, sucrose, and cornstarch incombination with binders, such as acacia, cornstarch, or gelatin,disintegrating agents such as potato starch or alginic acid, and alubricant such as stearic acid or magnesium stearate. Liquidpreparations are prepared by dissolving the active ingredient in anaqueous or non-aqueous pharmaceutically acceptable solvent, which mayalso contain suspending agents, sweetening agents, flavoring agents, andpreservative agents as are known in the art.

For parenteral administration the compounds may be dissolved in aphysiologically acceptable pharmaceutical carrier and administered aseither a solution or a suspension. Illustrative of suitablepharmaceutical carriers are water, saline, dextrose solutions, fructosesolutions, ethanol, or oils of animal, vegetative, or synthetic origin.The pharmaceutical carrier may also contain preservatives, buffers,etc., as are known in the art. When the compounds are being administeredintrathecally, they may also be dissolved in cerebrospinal fluid as isknown in the art.

The compounds of this invention will typically be administeredtopically. As used herein, topical refers to application of thecompounds (and optional carrier) directly to the skin or hair. Thetopical composition according to the present invention can be in theform of solutions, lotions, salves, creams, ointments, liposomes,sprays, gels, roller sticks, or any other method using micelles andpharmaceutically acceptable penetration enhancers Thus, a furtherembodiment relates to cosmetic or pharmaceutical compositions, inparticular dermatological compositions, which comprise at least one ofthe compounds corresponding to Formula I above. Such dermatologicalcompositions will contain from 0.001% to 10% w/w % of the compounds inadmixture with a dermatologically acceptable carrier, and moretypically, from 0.1 to 5 w/w % of the compounds. Such compositions willtypically be applied from 1 to 4 times daily.

The compositions according to the invention can also consist of solidpreparations constituting cleansing soaps or bars. These compositionsare prepared according to the usual methods.

The compounds can also be used for the hair in the form of aqueous,alcoholic or aqueous-alcoholic solutions, or in the form of creams,gels, emulsions or mousses, or alternatively in the form of aerosolcompositions also comprising a propellant under pressure. Thecomposition according to the invention can also be a hair carecomposition, and in particular a shampoo, a hair-setting lotion, atreating lotion, a styling cream or gel, a dye composition (inparticular an oxidation dye composition) optionally in the form ofcoloring shampoos, restructuring lotions for the hair, apermanent-waving composition (in particular a composition for the firststage of a permanent-waving operation), a lotion or gel for preventinghair loss, etc. The amounts of the various constituents in thedermatological compositions according to the invention are thoseconventionally used in the fields considered.

The medicinals and cosmetics containing the compounds of the inventionwill typically be packaged for retail distribution (i.e. an article ofmanufacture). Such articles will be labeled and packaged in a manner toinstruct the patient how to use the product. Such instructions willinclude the condition, which may be treated, duration of treatment,dosing schedule, etc.

The compounds of Formula I may also be admixed with any inert carrierand utilized in laboratory assays in order to determine theconcentration of the compounds within the serum, urine, etc., of thepatient as is known in the art. The compounds may also be used as aresearch tool.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention. The following examples and biological datais being presented in order to further illustrate the invention. Thisdisclosure should not be construed as limiting the invention in anymanner.

EXAMPLES Materials and Methods

Column chromatography was carried out on SiO₂ (40-63 mesh). LCMS datawere obtained using a Phenomenex Mercury Luna 3 μ C₁₈ column (2×10 mm,flow rate=1.5 mL min⁻¹) eluting with a 5% MeCN in H₂O-MeCN solution (4:1to 1:4) containing 0.1% HCO₂H over 2.55 minutes and diode arraydetection. The mass spectra were obtained employing an electrosprayionisation source in the positive (ES⁺) & negative (ES⁻) ion modes.Preparative mass-directed liquid chromatographic purification wascarried out utilizing a Waters Xterra 5μ C₁₈ column (19×50 mm, flowrate=20 mL min⁻¹) eluting with a 5% MeCN in H₂O-MeCN solution (4:1 to1:4) containing 0.1% HCO₂H over 7 minutes and diode array detection. ¹HNMR spectra were recorded at 400 MHz on a Varian Mercury spectrometer at27° C. The deuterated solvent was used as the lock, while the residualsolvent peak was employed as internal reference. Acronyms:DMAP=4-Dimethylaminopyridine;HATU=O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; NMP=1-Methyl-2-pyrrolidinone; PE=Petroleum ether(B.p.=60-80° C.); RT=Retention time.

Preparation of Starting Materials

Preparation 1:1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonylchloride

KOH (10.54 g, 188.0 mmol) was added to a solution of4-trifluoromethyl-1H-quinolin-2-one (4.00 g, 18.8 mmol) in DMF (160 mL).After 1 hour, the mixture was treated with MeI (11.7 mL, 188.0 mmol),then stirring was continued overnight. EtOAc (200 mL) was added,followed by saturated aqueous NH₄Cl to adjust the aqueous pH to 6.5.After separation of the layers, the aqueous phase was extracted furtherwith EtOAc (2×200 mL). The combined organic extracts were washed withH₂O (200 mL) and brine (200 mL), before being dried (MgSO₄). Filtration,solvent evaporation, and column chromatography (PE-EtOAc, 4:1 to 7:3)yielded 1-methyl-4-trifluoromethyl-1H-quinolin-2-one (4.00 g, 94%):δ_(H) ((CD₃)₂SO)=3.65 (s, 3H), 7.10 (s, 1H), 7.40 (t, 1H), 7.65-7.80 (m,3H). This compound (8.70 g, 38.3 mmol) was added portionwise withstirring over 20 min to fuming H₂SO₄ (30% oleum, 17.5 mL) at 84° C . Thebath temperature was raised to 120° C. for 1 hour, before being cooledback down to 20° C. Thereupon, the mixture was added slowly to saturatedaqueous NaCl (60 mL) and stirred for 30 min. The solid produced wascollected & dried under vacuum at 50° C. to give sodium1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonate:δ_(H)((CD₃)₂SO)=3.65 (s, 3H), 7.10 (s, 1H), 7.65 (d, 1H), 7.95 (dd, 1H),8.00 (d, 1H). This compound was suspended in MeCN-sulfolane (1:1, 52mL), before being treated with POCl₃ (18.8 mL, 201.7 mmol). The mixturewas heated to 88° C. for 1.5 hours, before being cooled to 20° C. over0.5 hour. On cooling to <5° C., ice cold H₂O (128 mL) was added, thetemperature being maintained below 7° C. The mixture was stirred at 0°C. for 20 minutes, then the solid formed was collected and washed withH₂O to afford, after drying, the title compound (9.62 g, 73%): δ_(H)(CDCl₃)=3.80 (s, 3H), 7.25 (s, 1H), 7.65 (d, 1H), 8.25 (dd, 1H), 8.50(d, 1H).Preparation 2: 2-Oxo-4-trifluoromethyl-2H-chromene-6-sulfonyl chloride

Sulfonation of 4-trifluoromethylchromen-2-one (5.00 g, 23.3 mmol),followed by NaCl treatment, as described in Preparation 1, producedsodium 2-oxo-4-trifluoromethyl-2H-chromene-6-sulfonate: δ_(H)((CD₃)₂SO)=7.10 (s, 1H), 7.45 (d, 1H), 7.90 (dd, 1H), 7.95 (d, 1H).Reaction of this compound with POCl₃ (10.3 mL, 110.5 mmol) provided thetitle compound (5.48 g, 75%): δ_(H) (CDCl₃)=7.00 (s, 1H), 7.70 (d, 1H),8.30 (dd, 1H), 8.40 (d, 1H).Preparation 3: 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonylChloride

4-Trifluoromethyl-1H-quinolin-2-one (5.00 g, 23.5 mmol) was treated withClSO₃H (3.1 mL, 47.0 mmol) at 0° C. The mixture was then heated withstirring to 140° C. for 7 hours. On cooling, ice-cold H₂O (50 mL) wasadded. The solid produced was collected and dried to give the titlecompound (2.93 g, 41%): δ_(H) (CDCl₃)=7.20 (s, 1H), 7.60 (d, 1H), 8.20(dd, 1H), 8.50 (d, 1H).

Preparation of Compounds of Formula I Example 1

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic AcidPhenylamide

A solution of1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonylchloride (Preparation 1, 65 mg, 200 μmol) in anhydrous DMF (1.5 mL) wascontacted with PhNH₂ (19 μL, 210 μmol), employing pyridine (17 μL, 220μmol) as base), before being stirred overnight under N₂. The reactionmixture was diluted with EtOAc (70 mL), before being washed with H₂O (30mL), 1 M HCl (30 mL), H₂O (30 mL), saturated aqueous NaHCO₃ (30 mL), H₂O(30 mL), & brine (30 mL). After drying (MgSO₄), the organic phase wasfiltered & concentrated to give a residue that was recrystallised fromEtOAc-PE to furnish the title compound (39 mg, 50%): δ_(H)((CD₃)₂SO)=3.60 (s, 3H), 7.00 (s, 1H), 7.10 (d, 2H), 7.15-7.20 (m, 3H),7.80 (d, 1H), 8.00-8.05 (m, 2H); m/z (ES⁺)=383.1 [M+H]⁺.

Example 2

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic Acid Phenylamide

Following the same procedure as Example 1, condensation of2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride(Preparation 3, 50 mg, 160 μmol) with PhNH₂ (15 μL, 168 μmol), employingpyridine (14 μL, 168 μmol) as base, gave the title compound (11 mg,17%): δ_(H) ((CD₃)₂SO)=7.00 (s, 1H), 7.05-7.10 (m, 3H), 7.20 (m, 2H),7.50 (d, 1H), 7.90 (dd, 1H), 8.00 (d, 1H); m/z (ES₊)=369.1 [M+H]⁺.

Example 3

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic Acid Benzylamide

Condensation of 2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonylchloride (Preparation 3, 16 mg, 51 μmol) with BnNH₂ (7 L, 54 μmol),employing NEt₃ (8 μL, 57 μmol) as base as delineated in Example 1, gavethe title compound (18 mg, 90%): δ_(H) ((CD₃)₂SO) =4.00 (d, 2H), 7.05(s, 1H), 7.10-7.20 (m, 5H), 7.50 (d, 1H), 7.95 (dd, 1H), 8.00 (d, 1H),8.30 (t, 1H); m/z (ES⁻)=381.0 [M-H]⁻.

Example 4-67

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic AcidAmnides, 2-oxo-4-trifluoromethyl-2H-chromene-6-sulfonic Acid Amides,(Table 1)

These compounds were prepared by solution phase parallel synthesis. Theappropriate amine as described by Formula III (30 μL of a 0.33 Msolution in NMP, 9.9 μmol), i-Pr₂NEt (20 μL of a 0.50 M solution in NMP,10.0 μmol), & the sulfonyl chloride of Formula II (50 μL of a 0.20 Msolution in NMP, 10.0 μmol) were mixed together in 1 well of a 96-wellplate using an automated liquid handler. After agitating for 66 h, thesolvents were evaporated off under reduced pressure & DMF (50 L) wasadded. To ensure dissolution, the mixture was shaken, before beingtreated with EtOAc (450 μL). Using automated liquid-liquid extractionequipment, the solution was washed with H₂O (150 μL) & 1% aqueous NaHCO₃(150 μL). The organic layer was concentrated to furnish the compoundsdisplayed in Table 1. Example CHEMISTRY Name RT Base Peak 4

1-Methyl-2-oxo-4- trifluoromethyl- dihydroquinoline-6-sulfonic acidbutylethylamide 1.98 391.2 [M + H]⁺ 5

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidbutyl(2-hydroxyethyl)- amide 1.70 407.2 [M + H]⁺ 6

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidbenzyl(2-hydroxyethyl)- amide 1.72 441.2 [M + H]⁺ 7

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2-hydroxyethyl)- pentylamide 1.78 421.2 [M + H]⁺ 8

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidbutyimethylamide 1.90 377.2 [M + H]⁺ 9

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic aciddibenzylamide 2.16 487.2 [M + H]⁺ 10

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidbenzylethylamide 2.00 425.2 [M + H]⁺ 11

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidmethylphenethylamide 1.98 425.2 [M + H]⁺ 12

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidmethylphenylamide 1.85 395.2 [M − H]⁻ 13

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidm-tolylamide 1.84 395.2 [M − H]⁻ 14

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidp-tolylamide 1.80 395.2 [M − H]⁻ 15

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4-ethynylphenyl)amide 1.81 405.2 [M − H]⁻ 16

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-ethylphenyl)amide 1.88 409.2 [M − H]⁻ 17

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4-ethylphenyl)amide 1.91 409.2 [M − H]⁻ 18

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2,6- dimethylphenyl)amide 1.85 409.2 [M − H]⁻ 19

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonicacid(2- hydroxymethylphenyl)amide 1.61 411.2 [M − H]⁻ 20

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2- methoxyphenyl)amide 1.78 411.2 [M − H]⁻ 21

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4- cyanomethylphenyl)amide 1.70 420.2 [M − H]⁻ 22

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidindan-5-ylamide 1.93 421.2 [M − H]⁻ 23

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidindan-4-ylamide 1.89 421.2 [M − H]⁻ 24

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-acetylphenyl)amide 1.68 423.2 [M − H]⁻ 25

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4- isopropylphenyl)amide 2.00 423.2 [M − H]⁻ 26

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidbenzo[1,3]dioxol-5- ylamide 1.75 425.1 [M − H]⁻ 27

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4-methylbipheny-3- yl)amide 2.00 471.2 [M − H]⁻ 28

1-Methyl-2-oxo-4- trifluoromethyl-1,2-dihydro- quinoline-6-sulfonic acid[3- (1-hydroxyethyl)phenyl]- amide 1.55 425.2 [M − H]⁻ 29

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3- methylsulfanylphenyl)amide 1.85 427.1 [M − H]⁻ 30

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(5-fluoro-2- methylphenyl)amide 1.82 413.2 [M − H]⁻ 31

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4-chlorophenyl)amide 1.89 415.4 [M − H]⁻ 32

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidisoquinolin-3-ylamide 1.74 434.1 [M + H]⁺ 33

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidquinolin-3-ylamide 1.68 434.1 [M + H]⁺ 34

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidquinolin-8-ylamide 1.86 434.2 [M + H]⁺ 35

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4-cyano-5- methylsulfanyl-2H-pyrazol- 3-yl)amide 1.78 442.1 [M − H]⁻ 36

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3,5-dimethoxyphenyl)- amide 1.77 441.2 [M − H]⁻ 37

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-isopropoxyphenyl)- amide 1.88 439.2 [M − H]⁻ 38

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-difluoromethoxy- phenyl)amide 1.85 447.1 [M − H]⁻ 39

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3- trifluoromethylphenyl)-amide 1.90 449.1 [M − H]⁻ 40

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic(4-methyl-2-oxo-2H- chromen-7-yl)amide 1.72 463.2 [M − H]⁻ 41

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-trifluoromethoxy- phenyl)amide 1.96 465.1 [M − H]⁻ 42

[4-(1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonylamino)phenyl]acetic acid ethyl ester 1.79 467.2 [M − H]⁻ 43

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-benzylphenyl)amide 1.97 471.2 [M − H]⁻ 44

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4-ethoxyphenyl)amide 1.82 425.2 [M − H]⁻ 45

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3,5-di-tert- butylphenyl)amide 2.26 493.3 [M − H]⁻ 46

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidbenzyl(4-methoxy- phenyl)amide 2.03 503.2 [M + H]⁺ 47

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid[4-(3- trifluoromethylpyrazol-1- yl)phenyl]amide 1.92 515.2 [M − H]⁻ 48

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3- methoxyphenyl)amide 1.76 411.2 [M − H]⁻ 49

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3,3- dimethylbutyl)amide 1.89 389.2 [M − H]⁻ 50

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidphenethylamide 1.85 409.2 [M − H]⁻ 51

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid4-methylbenzylamide 1.85 409.2 [M − H]⁻ 52

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2-methylbenzylamide 1.82 409.2 [M − H]⁻ 53

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2-cyclohex-1- enylethyl)amide 1.97 413.2 [M − H]⁻ 54

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2-thiophen-2- ylethyl)amide 1.78 415.1 [M − H]⁻ 55

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidindan-1-ylamide 1.86 421.2 [M − H]⁻ 56

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2-phenylpropyl)amide 1.85 423.2 [M − H]⁻ 57

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4-phenylbutyl)amide 1.95 437.2 [M − H]⁻ 58

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid[2-(2- methoxyphenyl)ethyl]amide 1.85 439.2 [M − H]⁻ 59

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid5-chloro-2- fluorobenzylamide 1.85 447.1 [M − H]⁻ 60

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid[2-(1H-indol-3- yl)ethyl]amide 1.75 448.2 [M − H]⁻ 61

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2-tert- butylsulfanylethyl)amide 1.87 421.2 [M − H]⁻ 62

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2-trifluoromethyl- benzylamide 1.88 463.2 [M − H]⁻ 63

1-Methyl-2-oxo-4- trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid[2-(2-chloro-6- fluorobenzylsulfanyl)ethyl]- amide 1.97 507.1 [M − H]⁻64

2-Oxo-4-trifluoromethyl-2H- chromene-6-sulfonic acid(pyridin-3-ylmethyl)amide 1.18 385.1 [M + H]⁺ 65

2-Oxo-4-trifluoromethyl-2H- chromene-6-sulfonic acid (1-methyl-1-phenylethyl)amide 1.95 410.2 [M − H]⁻ 66

2-Oxo-4-trifluoromethyl-2H- chromene-6-sulfonic acid 2-methylsulfanylbenzylamide 1.95 428.1 [M − H]⁻ 67

2-Oxo-4-trifluoromethyl-2H- chromene-6-sulfonic acid [2-(1H-indol-3-yl)ethyl]amide 1.87 435.2 [M − H]⁻

Examples 68-160

2Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic Acid Amides(Table 2)

Employing the procedure described above for Examples 4-67, theappropriate amine of Formula III (120 μL of a 0.33 M solution in NMP,39.6 μmol) was reacted with2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride (200μof a 0.20 M solution in NMP, 40.0 μmol) in the presence of i-Pr₂NEt (80μL of a 0.50 M solution in NMP, 40.0 μmol). Following evaporation of theNMP, the residues were dissolved in DMSO (450 L), before being subjectedto preparative mass-directed liquid chromatographic purification toprovide the compounds illustrated in Table 2. TABLE 2 Example CHEMISTRYName RT Base Peak 68

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic aciddibutylamide 2.01 405.2 [M + H]⁺ 69

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidbutylethylamide 1.87 377.2 [M + H]⁺ 70

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidisopropylmethylamide 1.66 347.2 [M − H]⁻ 71

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidbenzyl(2-hydroxyethyl)amide 1.65 425.2 [M − H]⁻ 72

6-(1,4-Dioxa-8- azaspiro[4.5]decane-8- sulfonyl)-4-trifluoromethyl-1H-quinolin-2-one 1.06 378.2 [M + H]⁺ 73

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidcyclopropylmethyl-propylamide 1.87 389.2 [M + H]⁺ 74

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2-hydroxyethyl)-pentylamide 1.68 405.2 [M − H]⁻ 75

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidcyclohexylmethylamide 1.86 389.2 [M + H]⁺ 76

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidbutylmethylamide 1.81 361.2 [M − H]⁻ 77

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2-cyanoethyl)methylamide 1.49 358.2 [M − H]⁻ 78

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidmethylphenethylamide 1.86 411.2 [M + H]⁺ 79

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-suifonic acidbenzylethylamide 1.88 411.2 [M + H]⁺ 80

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidbis(2-methoxyethyl)amide 1.57 409.1 [M + H]⁺ 81

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidpyridin-3-ylamide 1.34 370.1 [M + H]⁺ 82

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidm-tolylamide 1.73 381.1 [M − H]⁻ 83

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidp-tolylamide 1.71 381.1 [M − H]⁻ 84

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4-fluorophenyl)amide 1.68 385.1 [M − H]⁻ 85

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2,5-dimethyl-2H-pyrazol-3- yl)amide 1.38 387.2 [M + H]⁺ 86

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4-ethynylphenyl)amide 1.74 391.1 [M − H]⁻ 87

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-cyanophenyl)amide 1.62 392.1 [M − H]⁻ 88

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-ethylphenyl)amide 1.75 395.2 [M − H]⁻ 89

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4-ethylphenyl)amide 1.80 395.2 [M − H]⁻ 90

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2,6-dimethylphenyl)amide 1.68 395.1 [M − H]⁻ 91

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-hydroxymethylphenyl)amide 1.46 397.2 [M − H]⁻ 92

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2-methoxyphenyl)amide 1.63 397.1 [M − H]⁻ 93

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidquinolin-6-ylamide 1.30 420.2 [M + H]⁺ 94

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2,4-difluorophenyl)amide 1.69 403.1 [M − H]⁻ 95

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4-cyanomethylphenyl)amide 1.55 406.1 [M − H]⁻ 96

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidindan-5-ylamide 1.81 407.2 [M − H]⁻ 97

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4-isopropylphenyl)amide 1.85 409.2 [M − H]⁻ 98

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidbenzo[1,3]dioxol-5-ylamide 1.61 411.1 [M − H]⁻ 99

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4-methylbiphenyl-3-yl)amide 1.92 457.2 [M − H]⁻ 100

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid [3-(1-hydroxyethyl)phenyl]amide 1.47 411.1 [M − H]⁻ 101

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-methylsulfanylphenyl)amide 1.74 413.1 [M − H]⁻ 102

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2,5-dimethoxyphenyl)amide 1.65 427.1 [M − H]⁻ 103

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3,5-dimethoxyphenyl)amide 1.68 427.1 [M − H]⁻ 104

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(5-tert-butyl-2-methyl-2H- pyrazol-3-yl)amide 1.60 429.2 [M + H]⁺ 105

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-isopropoxyphenyl)amide 1.80 425.2 [M − H]⁻ 106

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid (3-difluoromethoxyphenyl)amide 1.72 433.1 [M − H]⁻ 107

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(5-phenyl-2H-pyrazol-3- yl)amide 1.63 435.1 [M + H]⁺ 108

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-methylcinnolin-5-yl)amide 1.46 435.1 [M + H]⁺ 109

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-trifluoromethylphenyl)amide 1.80 435.1 [M − H]⁻ 110

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2-bromophenyl)amide 1.72 449.0 [M + H]⁺ 111

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(4-methyl-2-oxo-2H-chromen-7- yl)amide 1.62 449.1 [M − H]⁻ 112

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid (3-trifluoromethoxyphenyl)amide 1.85 451.1 [M − H]⁻ 113

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid [4-(2-hydroxyethyl)phenyl]amide 1.45 413.2 [M + H]⁺ 114

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-benzyloxyphenyl)amide 1.90 473.1 [M − H]⁻ 115

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2-phenylsulfanylphenyl)amide 1.93 475.1 [M − H]⁻ 116

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-methoxyphenyl)amide 1.66 397.1 [M − H]⁻ 117

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidisopropylamide 1.43 333.1 [M − H]⁻ 118

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(thiophen-2-ylmethyl)amide 1.57 387.1 [M − H]⁻ 119

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2-methoxyethyl)amide 1.31 392.1 [M + H +MeO]⁺ 120

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidcyclopentylamide 1.57 359.1 [M − H]⁻ 121

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-methylbutyl)amide 1.68 361.1 [M − H]⁻ 122

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3,3-dimethylbutyl)amide 1.73 375.2 [M − H]⁻ 123

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidcyclohexylmethylamide 1.77 387.2 [M − H]⁻ 124

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2-methylbenzylamide 1.63 395.1 [M − H]⁻ 125

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(1-phenylethyl)amide 1.62 395.1 [M − H]⁻ 126

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidcycloheptylamide 1.72 387.2 [M − H]⁻ 127

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-isopropoxypropyl)amide 1.53 391.2 [M − H]⁻ 128

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidphenethylamide 1.63 395.2 [M − H]⁻ 129

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid4-fluorobenzylamide 1.59 399.1 [M − H]⁻ 130

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acidindan-1-ylamide 1.72 407.2 [M − H]⁻ 131

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2-phenylpropyl)amide 1.74 409.2 [M − H]⁻ 132

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2-cyclohex-1-enylethyl)amide 1.79 399.2 [M − H]⁻ 133

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2-thiophen-2-ylethyl)amide 1.64 401.1 [M − H]⁻ 134

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid[2-(1-methylpyrrolidin-2- yl)ethyl]amide 1.07 404.2 [M + H]⁺ 135

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid [2-(2-methoxyphenyl)ethyl]amide 1.66 425.1 [M − H]⁻ 136

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2-ethoxybenzylamide 1.73 425.2 [M − H]⁻ 137

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid5-fluoro-2-methylbenzylamide 1.68 413.1 [M − H]⁻ 138

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid3-chlorobenzylamide 1.68 415.1 [M − H]⁻ 139

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2,6-difluorobenzylamide 1.60 417.1 [M − H]⁻ 140

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2-chloro-4-fluorobenzylamide 1.69 433.1 [M − H]⁻ 141

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid3-chloro-2-fluorobenzylamide 1.66 433.1 [M − H]⁻ 142

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2-chloro-6-fluorobenzylamide 1.62 433.1 [M − H]⁻ 143

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2-methylsulfanylbenzylamide 1.68 427.1 [M − H]⁻ 144

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2-chloro-6-methylbenzylamide 1.68 429.1 [M − H]⁻ 145

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2,3-difluoro-4- methylbenzylamide 1.65 431.1 [M − H]⁻ 146

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid5-chloro-2-fluorobenzylamide 1.68 433.1 [M − H]⁻ 147

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid[2-(1H-indol-3-yl)ethyl]amide 1.60 436.1 [M + H]⁺ 148

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-hydroxy- methylbicyclo[2.2.1]hept-2-yl) 1.44 415.2 [M − H]⁻ 149

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid3,5-dimethoxybenzylamide 150

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid[2-(4-fluorophenyl)-1,1- dimethylethyl]amide 1.83 484.2 [M + H +MeO]⁺151

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2-difluoromethoxybenzylamide 1.66 447.1 [M − H]⁻ 152

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2-chloro-6-fluoro-3- methylbenzylamide 1.72 447.1 [M − H]⁻ 153

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2-trifluoromethylbenzylamide 1.75 449.1 [M − H]⁻ 154

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid[2-(2-chloro-6- fluorobenzylsulfanyl)ethyl]amide 1.82 493.1 [M − H]⁻ 155

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2-(2-hydroxymethyl- phenylsulfanyl)benzylamide 1.68 519.1 [M − H]⁻ 156

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2-bromobenzylamide 157

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(3-hydroxypropyl)amide 1.21 351.1 [M + H]⁺ 158

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid2-fluoro-5- trifluoromethylbenzylamide 1.70 467.1 [M − H]⁻ 159

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2,2-diphenylethyl)amide 1.84 471.2 [M − H]⁻ 160

2-Oxo-4-trifluoromethyl-1,2- dihydroquinoline-6-sulfonic acid(2-benzyloxycyclohexyl)amide 1.82 522.2 [M + H +MeO]⁺

Example 162 Biological Data

The compounds ability to antagonize the effects of androgen on theandrogen receptor were determined in the protocol described immediatelybelow. The results are shown in Table 3.

Experimental Procedure for AR Antagonist Cell Assay

Cell line: MDA-MB453-MMTV clone 54-19. This cell line is a stabletransfected cell line with MDA-MB453 cell background (human breast tumorcell expressing high level of androgen receptor). A MMTV minimalpromoter containing ARE was first cloned in front of a fireflyluciferase reporter gene. Then the cascade was cloned into transfectionvector pUV120puro. Electroporation method was used for transfectingMDA-MB-453 cell. Puromycin resistant stable cell line was selected.

Cell Culture Media and Reagents:

Culture medium: DMEM (high glucose, Gibco cat #: 11960-044), 10%FBS, and1% L-glutamine

Plating medium: DMEM (phenol red free), 10% charcoal treated HyCloneserum, 1% L-glutamine

Assay medium: DMEM (phenol red free), 1% charcoal treated HyClone serum,1% L-glutamine, and 1% penicillin/streptomycin

3× luciferase buffer: 2% beta-mercaptoethanol, 0.6% ATP, 0.0135%luciferine in cell lysis buffer

Assay Procedure:

-   1. Cells are maintained in culture medium, splitting cells when they    reach 80-90% confluence-   2. To test compounds, 10,000 cells/well are plated to opaque 96 cell    culture plate in 100 ul/well plating medium, culture for overnight    at 37° C. in cell culture incubator-   3. Carefully remove plating medium, then add 80 ul/well of    pre-warmed assay medium, add 10 ul/well testing compound (final    concentration at 10 uM or 1 uM), incubate at 37° C. for 30 minutes-   4. Add 10 ul/well freshly prepared DHT (final concentration at 100    pM) to each well, incubate at 37° C. for 17 hr (overnight)-   5. Add 50 ul/well 3× luciferase buffer, incubate at room temperature    for 5 minutes, then count on Luminometer    The fold induction over background by 100 pM DHT in the absence of    testing compounds is standardized as 100% and experimental result is    expressed as percentage of inhibition by testing compounds.

TABLE3 Example IC50 (uM)  12 >10  13 0.76  14 1.03  15 1.17  16 5.03  170.87  18 >10  19 >10  20 >10  21 0.99  22 4.47  23 >10  24 4.23  25 8.61 26 4.04  27 0.84  28 >10  29 3.72  30 >10  31 1.32  32 >10  33 >10 34 >10  35 >10  36 2.72  37 6.1  38 5.63  39 0.93  40 >10  41 3.86 42 >10  43 >10  44 3.76  45 >10  46 >10  47 2.96  48 1.13  49 >10  501.55  51 >10  52 >10  53 1.84  54 5.68  55 4.31  56 2.73  57 >10  58 5.4 59 >10  60 6.33  61 1.53  62 3.92  63 >10  4 10.6  5 >10  6 >10  7 >10 8 >10  9 >10  10 6.35  11 10  64 >10  65 >10  66 >10  67 >10 143 0.84136 0.58 156 2.16 145 >10 140 5.65 153 0.75 141 >10 151 0.73 159 1.56144 5.53 149 >10 146 6.54 152 >10 127 1.60 125 2.94 118 >10 158 6.61 1470.26 142 2.39 160 >10 122 1.03 119 4.69 154 2.18 123 8.51 155 1.94 1262.93 120 0.82 157 6.73 124 4.61 128 2.65 133 1.90 138 >10 129 >10 1350.17 137 3.76 139 2.98 132 0.21 131 0.35 130 1.03 117 2.34 121 0.28 1501.83 148 2.26 134 >10  71 1.31  73 0.55  75 5.72  76 0.21  77 1.04 80 >10  68 0.41  69 0.20  70 0.55  74 0.29  79 0.39  78 0.15  81 >10 82 0.83  83 1.14  84 7.08  85 >10  86 0.45  87 3.55  88 0.13  89 0.36 90 >10  91 3.13  92 >10  93 3.46  94 >10  95 0.84  96 0.14  97 0.20 98 >10  99 >10 100 >10 101 0.36 102 7.86 103 0.2 104 >10 105 0.45 1060.26 107 >10 108 >10 109 0.21 110 >10 111 >10 112 0.12 113 >10 114 >10115 8.13 116 0.34  72 >10

1. A compound of the formula:

in which: a. M is NZ or O; b. Z is represented by H or (C₁-C₄)alkyl; c.R¹ is represented by hydrogen, (C₁-C₂)alkyl, optionally substituted withone or more halogens, or (C₁-C₂)alkoxy, optionally substituted with 1 ormore halogens; d. R² is absent, or may represent up to 2 substituentsselected from the group consisting of halogen, nitrile, hydroxy,(C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₂)alkyl substituted with 1 or more halogens, (C₁-C₂)alkoxysubstituted with one or more halogens, SR⁴, and NR⁴R⁵; e. R⁴ isrepresented by hydrogen, optionally substituted phenyl, (C₁-C₄)alkyl, oroptionally substituted benzyl; f. R⁵ is represented by optionallysubstituted phenyl, optionally substituted heteroaryl, or optionallysubstituted heterocyclic g. A and B are each independently representedby a substituent selected from the group consisting of hydrogen,(C₁-C₆)alkyl optionally substituted with one or more halogens,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, optionally substituted (C₃-C₈)cycloalkyl, optionally substituted (C₅-C₈) cycloalkenyl, optionallysubstituted phenyl, optionally substituted cycloalkylphenyl, optionallysubstituted heterocyclic, optionally substituted heteroaryl,(C₁-C₆)alkylR⁶, —(CH₂)_(m)—R′—Y[—CH₂]_(n)—X—R⁸, and —(CH₂)_(q)CHX¹X²; h.R⁶ is represented by a substituent selected from the group consisting ofnitrile, OH, optionally substituted phenyl, optionally substitutedcyloalkylphenyl, optionally substituted heterocyclic, optionallysubstituted heteroaryl, optionally substituted (C₃-C₈) cycloalkyl,optionally substituted (C₅-C₈) cycloalkenyl, SR⁴, and NR⁴R⁵; i. R⁷ isabsent, or is represented by a substituent selected from the groupconsisting of optionally substituted (C₃-C₈) cycloalkyl, optionallysubstituted (C₅-C₈) cycloalkenyl, optionally substituted heteroaryl,optionally substituted heterocyclic, and optionally substituted phenyl;j. R⁸ is absent, or is represented by a substituent selected from thegroup consisting of (C₁-C₆)alkyl optionally substituted with one, ormore, halogens, optionally substituted (C₃-C₈) cycloalkyl, optionallysubstituted (C₅-C₈) cycloalkenyl, optionally substituted heteroaryl,optionally substituted heterocyclic, optionally substituted phenyl, andoptionally substituted cycloalkylphenyl; k. m is an integer selectedfrom 0, 1, 2, 3, or 4; l. Y is absent, or is represented by O, C(O),C(O)O, CH₂C(O)O, OH, SH, or S; m. n is represented by an integerselected from 0, 1, 2, 3, or 4; n. X is absent, or is represented by O,C(O), C(O)O, CH₂C(O)O, OH, SH, or S; o. q is represented by an integerselected from 0, 1, 2, 3, or 4; p. X¹ is represented by a substituentselected from the group consisting of optionally substituted (C₃-C₈)cycloalkyl, optionally substituted (C₅-C₈) cycloalkenyl, optionallysubstituted heteroaryl, optionally substituted heterocyclic, optionallysubstituted phenyl, and optionally substituted cycloalkylphenyl; q. X²is represented by a substituent selected from the group consisting ofoptionally substituted (C₃-C₈) cycloalkyl, optionally substituted(C₅-C₈) cycloalkenyl, optionally substituted heteroaryl, optionallysubstituted heterocyclic, optionally substituted phenyl, and optionallysubstituted cycloalkylphenyl and; r. the pharmaceutically acceptablesalts, solvates, and prodrugs thereof.
 2. The compounds of claim 1 inwhich R¹ is represented by trifluoromethyl.
 3. The compounds of claim 2in which M is NZ.
 4. The compounds of claim 2 in which B is hydrogen. 5.The compounds of claim 4 in which A is represented by optionallysubstituted phenyl.
 6. The compounds of claim 5 in which said phenyl issubstituted with a substituent selected from the group consisting ofmeta (C₁-C₄)alkyl and meta (C₁-C₂)alkoxy substituted with one or morehalogen atoms.
 7. The compounds of claim 4 in which A is (C₁-C₄)alkyl.8. The compounds of claim 4 in which A is C₁-C₆alkylR⁶ and R⁶ iscycloalkenyl.
 9. The compounds of claim 8 in which A is represented bycyclopentenylethyl.
 10. A method for inhibiting activation of theandrogen receptor comprising administering an effective amount of acompound according to claim 1 to a patient in need thereof.
 11. A methodfor the alleviating a condition selected from the group consisting ofalopecia, acne, oily skin, prostrate cancer, hirsutism, and benignprostate hyperplasia, comprising administering a compound according toclaim 1 to a patient in need thereof.
 12. A pharmaceutical compositioncomprising a compound according to claim 1 in admixture with 1, or more,pharmaceutically acceptable excipients.
 13. A topical pharmaceuticalformulation comprising a compound according to claim 1 in admixture with1, or more, pharmaceutically acceptable excipients suitable for dermalapplication.
 14. An article of manufacture comprising a compoundaccording to claim 1 packaged for retail distribution which advises aconsumer how to utilize the compound to alleviate a condition selectedfrom the group consisting of acne, alopecia, and oily skin.
 15. Acompound according to claim 1 selected from the group consisting of:1-Methyl-2-oxo4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidphenylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid phenylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbenzylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbutylethylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbutyl(2-hydroxyethyl)-amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbenzyl(2-hydroxyethyl)-amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-hydroxyethyl)-pentylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbutylmethylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic aciddibenzylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbenzylethylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidmethylphenethylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidmethylphenylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidm-tolylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidp-tolylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-ethynylphenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-ethylphenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-ethylphenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2,6-dimethylphenyl)arnide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-hydroxymethylphenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-methoxyphenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-cyanomethylphenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidindan-5-ylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidindan-4-ylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-acetylphenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-isopropylphenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbenzo[1,3]dioxol-5-ylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-methylbiphenyl-3-yl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydro-quinoline-6-sulfonic acid[3-(1-hydroxyethyl)phenyl]-amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-methylsulfanylphenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(5-fluoro-2-methylphenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-chlorophenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidisoquinolin-3-ylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidquinolin-3-ylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidquinolin-8-ylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-cyano-5-methylsulfanyl-2H-pyrazol-3-yl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3,5-dimethoxyphenyl)-amide;1-Methyl-2-oxo4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-isopropoxyphenyl)-amide;1-Methyl-2-oxo4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-difluoromethoxy-phenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-trifluoromethylphenyl)-amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-methyl-2-oxo-2H-chromen-7-yl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-trifluoromethoxy-phenyl)amide;[4-(1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonylamino)phenyllaceticacid ethyl ester;1-Methyl-2-oxo4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-benzylphenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-ethoxyphenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3,5-di-tert-butylphenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbenzyl(4-methoxy-phenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[4-(3-trifluoromethylpyrazol-1-yl)phenyl]amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-methoxyphenyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3,3-dimethylbutyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidphenethylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid4-methylbenzylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-methylbenzylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-cyclohex-1-enylethyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-thiophen-2-ylethyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidindan-1-ylamide;1-Methyl-2-oxo4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-phenylpropyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-phenylbutyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[2-(2-methoxyphenyl)ethyl]amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid5-chloro-2-fluorobenzylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[2-(1H-indol-3-yl)ethyl]amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-tert-butylsulfanylethyl)amide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-trifluoromethyl-benzylamide;1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[2-(2-chloro-6-fluorobenzylsulfanyl)ethyl]-amide;2-Oxo-4-trifluoromethyl-2H-chromene-6-sulfonic acid(pyridin-3-ylmethyl)amide;2-Oxo-4-trifluoromethyl-2H-chromene-6-sulfonic acid(1-methyl-1-phenylethyl)amide;2-Oxo-4-trifluoromethyl-2H-chromene-6-sulfonic acid2-methylsulfanylbenzylamide;2-Oxo-4-trifluoromethyl-2H-chromene-6-sulfonic acid[2-(1H-indol-3-yl)ethyl]amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic aciddibutylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid butylethylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidisopropylmethylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbenzyl(2-hydroxyethyl)amide;6-(1,4-Dioxa-8-azaspiro[4.5]decane-8-sulfonyl)-4-trifluoromethyl-1H-quinolin-2-one;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidcyclopropylmethyl-propylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-hydroxyethyl)-pentylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidcyclohexylmethylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbutylmethylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-cyanoethyl)methylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidmethylphenethylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbenzylethylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbis(2-methoxyethyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidpyridin-3-ylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidm-tolylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid p-tolylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-fluorophenyl)amnide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2,5-dimethyl-2H-pyrazol-3-yl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-ethynylphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-cyanophenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-ethylphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-ethylphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2,6-dimethylphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-hydroxymethylphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-methoxyphenyl)amnide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidquinolin-6-ylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2,4-difluorophenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-cyanomethylphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidindan-5-ylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (4-isopropylphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbenzo[1,3]dioxol-5-ylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-methylbiphenyl-3-yl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[3-(1-hydroxyethyl)phenyl]amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-methylsulfanylphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2,5-dimethoxyphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3,5-dimethoxyphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-isopropoxyphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-difluoromethoxyphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(5-phenyl-2H-pyrazol-3-yl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-methylcinnolin-5-yl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-trifluoromethylphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-bromophenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-methyl-2-oxo-2H-chromen-7-yl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-trifluoromethoxyphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[4-(2-hydroxyethyl)phenyl] amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-benzyloxyphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-phenylsulfanylphenyl)amide;2-Oxo4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-methoxyphenyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidisopropylamide; 2-Oxo4-trifluoromethyl-1 ,2-dihydroquinoline-6-sulfonicacid (thiophen-2-ylmethyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-methoxyethyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidcyclopentylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-methylbutyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3,3-dimethylbutyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidcyclohexylmethylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-methylbenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(1-phenylethyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidcycloheptylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-isopropoxypropyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidphenethylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid 4-fluorobenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidindan-1-ylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (2-phenylpropyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-cyclohex-1-enylethyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-thiophen-2-ylethyl)amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[2-(1-methylpyrrolidin-2-yl)ethyl]amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[2-(2-methoxyphenyl)ethyl]amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-ethoxybenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid5-fluoro-2-methylbenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid3-chlorobenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2,6-difluorobenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-chloro-4-fluorobenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid3-chloro-2-fluorobenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-chloro-6-fluorobenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-methylsulfanylbenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-chloro-6-methylbenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2,3-difluoro-4-methylbenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid5-chloro-2-fluorobenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[2-(1H-indol-3-yl)ethyl]amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-hydroxymethylbicyclo[2.2.1]hept-2-yl);2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid3,5-dimethoxybenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[2-(4-fluorophenyl)-1,1-dimethylethyl]amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-difluoromethoxybenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-chloro-6-fluoro-3-methylbenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-trifluoromethylbenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[2-(2-chloro-6-fluorobenzylsulfanyl)ethyl]amide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-(2-hydroxymethylphenylsulfanyl)benzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-bromobenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-hydroxypropyl)aniide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-fluoro-5-trifluoromethylbenzylamide;2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2,2-diphenylethyl)amide; and2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-benzyloxycyclohexyl)amide.